Ataxia telangiectasia (A-T) is an autosomal recessive inherited disease characterized by immunodeficiency, developmental abnormalities, neurodegenerative changes and an approximately 100 fold increased incidence in cancer of earlier than usual onset, together with abnormal radiosensitivity and increased chromosomal breakage in homozygotes. Indeed, malignancies are the leading cause of early mortality in A-T. Little is known about the biological mechanisms that are impaired in this disease and most of the information so far derives from cell biology studies using cells cultured from A-T patients. These studies show that A-T plays a role in the checkpoint regulating cell cycle progression following DNA damage and they suggest that one of the normal functions of the gene is either monitoring DNA damage or signaling and inhibiting cell cycle progression following DNA damage. This is reminiscent of the activity of some of the known major genetic alterations responsible for cancer by increasing genetic instability as a result of impairment of the ability of cells to respond properly to DNA damage. The recent cloning of the human ATM (Ataxia-Telangiectasia- Mutated) gene and the identification of a family of ATM-like proteins allows us to pursue a study of its biochemical function in the signaling events normally leading to cell cycle arrest. We propose to exploit the Xenopus model system, in which the biochemical reactions governing cell cycle regulation and checkpoint control can be approached in vitro in cell-free extracts that recapitulate genuine cell cycle transitions and checkpoint signaling. We propose experiments that aim at understanding the function of A-T in regulating the cell cycle following DNA damage. From these studies, we anticipate gaining major insights into how A-T mutations participate in increasing the incidence in cancer in A-T patients and to identify new targets for therapy of this disease as well as for cancer therapy in general.